Genetic Variant NM_001957.4:c.1143+54A>C (chr4-147540539-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001957.4(EDNRA):c.1143+54A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,271,564 control chromosomes in the GnomAD database, including 168 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 113 hom., cov: 31)

Exomes 𝑓: 0.0020 ( 55 hom. )

Consequence

EDNRA
NM_001957.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.17

Publications

3 publications found

Variant links:

Genes affected

EDNRA (HGNC:3179): (endothelin receptor type A) This gene encodes the receptor for endothelin-1, a peptide that plays a role in potent and long-lasting vasoconstriction. This receptor associates with guanine-nucleotide-binding (G) proteins, and this coupling activates a phosphatidylinositol-calcium second messenger system. Polymorphisms in this gene have been linked to migraine headache resistance. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

EDNRA links:

TMEM184C-DT (HGNC:55544): (TMEM184C divergent transcript)

TMEM184C-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 4-147540539-A-C is Benign according to our data. Variant chr4-147540539-A-C is described in ClinVar as Benign. ClinVar VariationId is 1175503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0669 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001957.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EDNRA	NM_001957.4	MANE Select	c.1143+54A>C	intron	N/A	NP_001948.1	P25101-1
EDNRA	NM_001166055.2		c.816+54A>C	intron	N/A	NP_001159527.1	P25101-4
EDNRA	NR_045958.2		n.1294+54A>C	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EDNRA	ENST00000651419.1	MANE Select	c.1143+54A>C	intron	N/A	ENSP00000498969.1	P25101-1
EDNRA	ENST00000324300.10	TSL:1	c.1143+54A>C	intron	N/A	ENSP00000315011.5	P25101-1
EDNRA	ENST00000506066.1	TSL:1	c.816+54A>C	intron	N/A	ENSP00000425281.1	P25101-4

Frequencies

GnomAD3 genomes

AF:

0.0200

AC:

3047

AN:

152220

Hom.:

113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0692

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00818

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.0172

GnomAD4 exome

AF:

0.00197

AC:

2205

AN:

1119226

Hom.:

AF XY:

0.00169

AC XY:

957

AN XY:

566114

show subpopulations

African (AFR)

AF:

0.0649

AC:

1665

AN:

25672

American (AMR)

AF:

0.00444

AC:

157

AN:

35364

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22990

East Asian (EAS)

AF:

0.00

AC:

AN:

36046

South Asian (SAS)

AF:

0.0000986

AC:

AN:

70962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47412

Middle Eastern (MID)

AF:

0.00234

AC:

AN:

4278

European-Non Finnish (NFE)

AF:

0.000197

AC:

163

AN:

827850

Other (OTH)

AF:

0.00417

AC:

203

AN:

48652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

199

298

398

497

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0200

AC:

3047

AN:

152338

Hom.:

113

Cov.:

AF XY:

0.0194

AC XY:

1443

AN XY:

74520

show subpopulations

African (AFR)

AF:

0.0690

AC:

2866

AN:

41544

American (AMR)

AF:

0.00816

AC:

125

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68040

Other (OTH)

AF:

0.0170

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

149

297

446

594

743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0140

Hom.:

Bravo

AF:

0.0223

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.6

(source)

DANN

Benign

0.58

PhyloP100

2.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over